Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas Journal Article

Authors: Geyer, F. C.; Li, A.; Papanastasiou, A. D.; Smith, A.; Selenica, P.; Burke, K. A.; Edelweiss, M.; Wen, H. C.; Piscuoglio, S.; Schultheis, A. M.; Martelotto, L. G.; Pareja, F.; Kumar, R.; Brandes, A.; Fan, D.; Basili, T.; Da Cruz Paula, A.; Lozada, J. R.; Blecua, P.; Muenst, S.; Jungbluth, A. A.; Foschini, M. P.; Wen, H. Y.; Brogi, E.; Palazzo, J.; Rubin, B. P.; Ng, C. K. Y.; Norton, L.; Varga, Z.; Ellis, I. O.; Rakha, E. A.; Chandarlapaty, S.; Weigelt, B.; Reis-Filho, J. S.
Article Title: Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas
Abstract: Adenomyoepithelioma of the breast is a rare tumor characterized by epithelial-myoepithelial differentiation, whose genetic underpinning is largely unknown. Here we show through whole-exome and targeted massively parallel sequencing analysis that whilst estrogen receptor (ER)-positive adenomyoepitheliomas display PIK3CA or AKT1 activating mutations, ER-negative adenomyoepitheliomas harbor highly recurrent codon Q61 HRAS hotspot mutations, which co-occur with PIK3CA or PIK3R1 mutations. In two-and three-dimensional cell culture models, forced expression of HRASQ61R in non-malignant ER-negative breast epithelial cells with or without a PIK3CA H1047R somatic knock-in results in transformation and the acquisition of the cardinal features of adenomyoepitheliomas, including the expression of myoepithelial markers, a reduction in E-cadherin expression, and an increase in AKT signaling. Our results demonstrate that adenomyoepitheliomas are genetically heterogeneous, and qualify mutations in HRAS, a gene whose mutations are vanishingly rare in common-type breast cancers, as likely drivers of ER-negative adenomyoepitheliomas. © 2018 The Author(s).
Journal Title: Nature Communications
Volume: 9
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2018-05-08
Start Page: 1816
Language: English
DOI: 10.1038/s41467-018-04128-5
PROVIDER: scopus
PMCID: PMC5940840
PUBMED: 29739933
Notes: Article -- Export Date: 1 June 2018 -- Source: Scopus
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